Further analyses revealed distinct populations of patients who responded better to nivolumab monotherapy, specifically those with PD-L1-positive and HPV-positive HNSCC. In these groups, the reduction in the risk of death with nivolumab was near 50% versus investigator's choice of therapy.

"Nivolumab is a new standard-of-care option for patients with recurrent or metastatic head and neck squamous cell carcinoma after platinum-based therapy," said lead investigator Robert L. Ferris, MD, PhD, from the University of Pittsburgh Medical Center Cancer Center. "Nivolumab is the first agent to demonstrate a significant improvement in survival in patients with head and neck squamous cell carcinoma who progress after platinum-based therapy in a global, phase III comparative trial."

In the trial, 361 patients with cancer of the oral cavity, pharynx, or larynx were randomized in a 2:1 ratio to receive nivolumab (n = 240) or investigator's choice of cetuximab (12.4%), methotrexate (44.6%), or docetaxel (43%; N = 121). Nivolumab was administered intravenously at 3 mg/kg every 2 weeks. Cetuximab was administered at 400 mg/m2 for the first dose followed by 250 mg/m2 weekly. Methotrexate was administered at 40 mg/m2 weekly. Docetaxel was administered at 30 mg/m2 weekly.

The median age of patients in the trial was 60 years, and 31.3% were ≥65 years of age. The majority of patients were male (83%), Caucasian (83%), and had an ECOG PS of 1 (78.4%). Most patients received ≥2 prior systemic therapies (54.8%), and over 90% had received prior radiation therapy. HPV status was known for 49.3% of patients, using p16 status, and PD-L1 expression was available for 72% of enrolled patients.

The primary endpoint was OS, with secondary outcome measures focused on response rates and progression-free survival (PFS). The study was initiated in May 2014 and was not scheduled to complete until October 2016; however, it was stopped early after an independent monitoring panel determined the primary endpoint was met with the anti–PD-1 agent versus the investigator's choice of therapy.

The 1-year OS rates were 36% with nivolumab (95% CI, 28.5-43.4) compared with 16.6% for investigator’s choice (95% CI, 8.6-26.8). Similar improvements in survival were seen across demographic subgroups. The 6-year PFS rates were 19.7% for nivolumab and 9.9% for investigator's choice of therapy.

The ORR in the nivolumab arm consisted of 6 complete responses (2.5%) and the stable disease (SD) rate was 22.9%. In the investigator's choice arm, 1 patient had a complete response and the SD rate was 35.5%.

"Nivolumab doubled the 1-year survival rate, from 36% with nivolumab to 17% for investigator's choice of therapy," said Ferris. "Nivolumab demonstrated a survival benefit in the overall study population, regardless of PD-L1 expression or p16 status."

Those with PD-L1 expression on ≥1% of cells experienced a median OS of 8.7 months with nivolumab compared with 4.6 months in the control arm (HR, 0.55; 95% CI, 0.36-0.83). Those who tested negative for PD-L1 had a median OS of 5.7 months with nivolumab versus 5.8 months in the control arm (HR, 0.89; 95% CI, 0.54-1.45).

In those with PD-L1 expression on ≥5% cells, the median OS was 8.8 versus 4.6 months for nivolumab and investigator's choice, respectively (HR, 0.50; 95% CI, 0.30-0.83). For those with ≥10% expression, median OS was and 8.7 versus 5.2 months, for nivolumab and the control, respectively (HR, 0.56; 95% CI, 0.31-0.99).

"Magnitude of OS benefit of nivolumab versus investigator's choice was greater in patients expressing PD-L1, and increasing PD-L1 expression did not result in further benefit," said Ferris.

In patients with tumors that expressed PD-L1 on ≥1% of cells, the ORR was 17% with nivolumab compared with 1.6% with investigator's choice. In those with ≥5% and ≥10% expression, the ORRs were 22.2% versus 2.3% and 27.9% versus 2.9%, for nivolumab and the control arm, respectively. In the PD-L1-negative group, the ORR was 12.3% with nivolumab and 10.5% with investigator's choice of therapy.

HPV status also played a role in the responses experienced by patients treated with nivolumab. In the HPV-positive group, the median OS was 9.1 months with nivolumab compared with 4.4 months with investigator's choice (HR, 0.56; 95% CI, 0.32-0.99). In the HPV-negative arm, the median OS with nivolumab was 7.5 versus 5.8 months (HR, 0.73; 95% CI, 0.42-1.25).

Those with PD-L1 expression ≥1% and HPV-positive HNSCC had a median OS of 8.8 months with nivolumab and 3.9 months in the control arm (HR, 0.50; 95% CI, 0.21-1.19). In those with ≥1% PD-L1 expression and HPV-negative disease, the median OS was 8.8 versus 5.6 months, for nivolumab and control, respectively (HR, 0.44; 95% CI, 0.18-1.10).

For those with PD-L1-negative and HPV-positive disease, the median OS was 10.0 versus 6.4 months (HR, 0.55; 95% CI, 0.22-1.39). In those with PD-L1-negative/HPV-negative HNSCC, the median OS was 7.1 months with nivolumab and 7.4 months with investigator's choice of therapy (HR, 0.82; 95% CI, 0.31-2.19).

AEs were significantly less with nivolumab versus investigator's choice. Overall, grade 3/4 events were experienced by 13.1% of patients treated with nivolumab versus 35.1% for investigator’s choice. All-grade AEs were experienced by 58.9% of patients treated with nivolumab compared with 77.5% with investigator's choice.

The most common grade 3/4 AEs with nivolumab were fatigue (2.1%), anemia (1.3%), and asthenia (0.4%). For investigator's choice, the most common grade 3/4 AEs were anemia (4.5%), alopecia (2.7%), fatigue (2.7%), diarrhea (1.8%), asthenia (1.8%), and mucosal inflammation (1.8%).

There were 2 treatment-related deaths in the nivolumab arm related to pneumonitis and hypercalcemia. In the investigator's choice arm, there was 1 death related to lung infection.

"There were fewer treatment-related adverse events with nivolumab versus investigator's choice of therapy," said Ferris. "Nivolumab stabilized patient-reported outcomes while investigator's choice led to meaningful declines in function and worsening of symptoms."